P798: DIAMOND BLACKFAN ANEMIA MAY ESCAPE DIAGNOSIS UP TO ADULTHOOD; A REPORT FROM THE UPDATED GREEK REGISTRY
Authors: Polyxeni Delaporta, Christalena Sofocleous, Stavros Glentis, Danai Veltra, Sophia Polychronopoulou, Lydia Kossiva, Alexandros Makis, Marina Economou, Nikolaos Katzilakis, Eftychia Steiakaki, Theodoros Marinakis, Stavroula Kostaridou, Antonis Kattamis
Journal: HemaSphere (2023)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Diamond Blackfan Anemia (DBA), is a rare bone marrow failure syndrome presenting with normochromic macrocytic anemia, reticulocytopenia, significantly reduced erythroid precursors in an otherwise normocellular bone marrow, and frequently associated with congenital malformations. In 60 to 70% of DBA cases, the underlying ribosomopathy is attributed to pathogenic variants in one of either the 26, ribosomal protein (RP) genes, or TSR2 or GATA1, X-linked genes. Aims: To present the updated Greek DBA registry. The initial report of the registry, organized in 2014, concerned 17 patients. Methods: Genotypes and clinical data, including clinical features, medical history and therapeutic interventions of DBA patients were captured. Molecular analysis was performed, initially by Sanger Sequencing of RPS19, RPL5, and RPL11 genes during the period up to 2018, followed by Next-Generation Sequencing (NGS) approaches, targeted gene panel and Whole Exome Sequencing (WES), thereafter. Results: The updated DBA registry included 14 additional patients, comprising a total of 31 patients (18 males/13 females). Patients’ characteristics are summarized in Table 1. Congenital anomalies were observed in 19/31 (61%) of the patients. Craniofacial malformations (including cleft or lip palate) (n=10, 32%), hand (including thumb), and cardiac anomalies (8 patients each, 25.8%) were the most prevalent. Of note is that five patients, who had an early onset of anemia, were diagnosed, clinically and genotypically, in adulthood (median age at diagnosis, 39.6±8.5 years). These patients were (a) a 46 years old female (P1) with mild macrocytic anemia (Hb: 11.9 g/dL, MCV: 104.5 fl) and leukopenia WBC: 2700/μL (b) a 32 year old male (P2) with macrocytic anemia (Hb: 9.3 g/dL, MCV: 101.8 fl, RET: 0.4%, HbF: 8%) responsive to 0.06 mg/kg/day of prednisolone (Hb 10.5 g/L) and bilateral triphalangeal thumbs, (c) P2’s, 65 year old father (P3) presenting with normochromic normocytic anemia (Hb 12.3g/dl), bilateral triphalangeal thumbs and hexadactyly, and a right ocular melanoma without hepatic metastases (d) a 36 years old female (P4) with microcytic anemia (Hb: 8.5 g/dL, MCV: 72.5 fl, HbA 2 4%, HbF: 2.5%) responsive to 0.18 mg/kg/day prednisolone (Hb of 10.4 g/dL), bilateral triphalangeal thumbs and low IgG (728mg/dl) and (e) a 30 year old male (P5) with transfusion dependent anemia, increased HbF and a history of presumptive MDS at the age of 4 years. Causative variants in known DBA genes were detected in 22/31 patients (67.7%), and include a large deletion encompassing RPL35A gene and four novel variants {RPS7:c.291G>A:p.Gln97= (P1), RPS17:c.156-1G>A, RPS26:c.181 + 1delG, RPL35A: c.204_205 del p.Arg68SerTer27). Adult patients 2 and 3 had the RPL11:c.124 C>T:p.Gln42Ter variant, patient 4 the RPL11:c.94-97delAGAC:p.Arg32X along with an HBB variant (c.93-21G>A) and patient 5 the RPS19:c.185G>A:p.Arg62Gln variant Summary/Conclusion: The clinical course of patients’ registered is similar to previous international and national reports. DBA diagnosis should be considered in severe anemia as well as in moderate anemia accompanied by congenital malformation, even in adult patients. Accurate diagnosis is facilitated by NGS techniques and is essential for optimal intervention and guidance.Keywords: Gene mutation, Diamond-Blackfan anemia, Adult